ORGANIC LETTERS
Anionic N-Fries Rearrangement of N-Carbamoyl Diarylamines to Anthranilamides. Methodology and Application to Acridone and Pyranoacridone Alkaloids
2006 Vol. 8, No. 6 1133-1136
Stephen L. MacNeil,† Brian J. Wilson,‡ and Victor Snieckus* Department of Chemistry, Queen’s UniVersity, Kingston, Ontario K7L 3N6, Canada
[email protected] Received December 30, 2005
ABSTRACT
A general alkyllithium/LDA-mediated rearrangement of N-carbamoyl diarylamines 7a−g into the anthranilamides 8a−g and 9a−g (Table 1) is presented and applied to a regioselective efficient construction of acridone (17) and pyranoacridone (18) alkaloids (Scheme 4).
Recent efforts in our laboratories aim to develop new carbanionic aromatic chemistry which, by moderating the harsh conditions and circumventing rules of classical electrophilic substitution, offer complementary but also new, regioselective, and mild methods for the construction of polysubstituted aromatics, heteroaromatics, and their condensed counterparts.1 To illustrate by a reaction that conceptually applies also for other heterocycles,1g-j the LDAinduced conversion 1 f 2 (Scheme 1), apparently driven by combined directed ortho metalation (DoM)2 and Complex Induced Proximity Effect (CIPE),3 is an anionic equivalent of the Lewis acid-catalyzed Friedel-Crafts reaction; the latter, if applied to 1, provides the isomeric product 3 due to the strong EDG nature of the OMe group.4,5 During the course of one of these studies,1g we uncovered an alkyllithium-mediated transformation of N-protected diarylamines 5 (Z ) NAr, DMG ) CO2tBu) into N-aryl anthranilates 6a † Current address: Department of Chemistry, Wilfrid Laurier University, Waterloo, ON N2L 3C5, Canada. ‡ Current address: GlaxoSmithKline Research & Development, Research Triangle Park, NC 27709.
10.1021/ol053162e CCC: $33.50 Published on Web 02/24/2006
© 2006 American Chemical Society
(Scheme 2), constituting an N-analogue of the anionic orthoFries rearrangement of aryl O-carbamates, 5 (Z ) O, DMG ) CONR2), into the salicylamides.1a,6-8 We subsequently found that the corresponding rearrangement of the N-CONEt2 derivative, 5 (Z ) NAr, DMG ) CONEt2), into the anthranilamides 6b proceeded with greater efficiency and
Scheme 1. Regiochemical Complementarity of Carbanion-Mediated and Lewis Acid-Catalyzed Cyclization Reactions
Scheme 2. Alkyllithium-Mediated Transformation of N-Protected Diarylamines into N-Aryl Anthranilates and N-Aryl Anthranilamides
series,8 the prototype N-carbamoyl diphenylamine 7a10 was subjected to standard t-BuLi/TMEDA conditions to afford product 9a in excellent yield (Table 1, entry 1).11 Application
Table 1. Anionic Ortho N-Fries Rearrangement of N-CONEt2 Diarylamines 7a-g
regioselectivity. Herein we report on the scope and regioselectivity of this new version of the anionic N-ortho-Fries rearrangement,9 show its link to further DoM chemistry, and demonstrate its application to the synthesis of acridone and pyranoacridone alkaloids. Pursuant of improvement of the anionic N-Fries rearrangement, and based on preliminary results from the N-BOC (1) (a) Anionic ortho-Fries: Sibi, M. P.; Snieckus, V. J. Org. Chem. 1983, 48, 1935-1937. (b) Vinylogous anionic ortho-Fries: Kalinin, A. V.; Miah, M. A. J.; Chattopadhyay, S.; Tsukazaki, M.; Wicki, M.; Nguen, T.; Coelho, A. L.; Kerr, M.; Snieckus, V. Synlett 1997, 7, 839-841. (c) 1,5OfO CONEt2 translocation: Chauder, B. A.; Kalinin, A. V.; Taylor, N. J.; Snieckus, V. Angew. Chem., Int. Ed. 1999, 38, 1435-1438. (d) Remote anionic Fries: Wang, W.; Snieckus, V. J. Org. Chem. 1992, 57, 424-426. (e) 1,2 Wittig versus 1,5-OfO CONEt2 translocation: Zhang, P.; Gawley, R. E. J. Org. Chem. 1993, 12, 3222-3223. (f) Carbamoyl BakerVenkatarman reaction: Kalinin, A. V.; da Silva, A. J. M.; Lopes, C. C.; Lopes, R. S. C.; Snieckus, V. Tetrahedron Lett. 1998, 39, 4995-4998. (g) Anionic Friedel-Crafts equivalents: To acridones: MacNeil, S. L.; Gray, M.; Briggs, L. E.; Li, J. J.; Snieckus, V. Synlett 1998, 4, 419-421. MacNeil, S. L.; Gray, M.; Briggs, L. E., Snieckus, V. In preparation. (h) To xanthones: Familoni, O. B.; Ionica, I.; Bower, J. F.; Snieckus, V. Synlett 1997, 9, 1081-1083. (i) To thiaxanthones: Beaulieu, F.; Snieckus, V. J. Org. Chem. 1994, 59, 6508-6509. (j) To phosphorinones: Gray, M.; Chapell, B. J.; Taylor, N. J.; Snieckus, V. Angew. Chem., Int. Ed. Engl. 1996, 35, 1558-1560. (k) Anionic OfR- and β-vinyl carbamoyl translocation: Reed, M. A.; Chang, M. T.; Snieckus, V. Org. Lett. 2004, 6, 22972300. (2) (a) Snieckus, V. Chem. ReV. 1990, 90, 879-933. (b) Hartung, C. G.; Snieckus, V. In Modern Arene Chemistry; Astruc, D., Ed.; WileyVCH: Weinheim, Germany, 2002; pp 330-367. (3) Whisler, M. C.; MacNeil, S.; Snieckus, V.; Beak, P. Angew. Chem., Int. Ed. 2004, 43, 2206-2225. (4) For a closely related example, see: Iwao, M.; Reed, N.; Snieckus, V. J. Am. Chem. Soc. 1982, 104, 5531-5533. (5) For general effects of m-EDG on Friedel-Crafts chemistry, see: Taylor, R. In Electrophilic Aromatic Substitution; Wiley: New York, 1990; p 236. For examples, see: Sargent, M. V. J. Chem. Soc., Perkin Trans. 1 1987, 2553. Fu, J.-m.; Zhao, B.-p.; Sharp. M. J.; Snieckus, V. Can. J. Chem. 1994, 72, 227-236. Sharp, M. J. M.Sc. Thesis, University of Waterloo, 1986. (6) For other phenol- and aniline-based ortho anionic rearrangements, at times effected not by DoM but by metal-halogen exchange, see, inter alia: (a) ArOP(O)(OR)2: Cambie, R. C.; Plamer, B. D. Aust. J. Chem. 1982, 35, 827-837 and references therein. Melvin, L. S. Tetrahedron Lett. 1981, 22, 3375-3376. Dhawan, B.; Redmore, D. Phosphorus, Sulfur Silicon Relat. Elem. 1991, 61, 183-187 and references therein. (b) ArOCOR: Hellwinkel, D.; La¨mmerzahl, F.; Hofmann, G. Chem. Ber. 1983, 116, 33753405 and references therein. (c) ArOSiR3: Billedeau, R. J.; Sibi, M. P.; Snieckus, V. Tetrahedron Lett. 1983, 24, 4515-4518. (d) ArN(R)P(O)(OR)2: Jardine, A. M.; Vather, S. M. J. Org. Chem. 1988, 53, 3983-3985. (e) ArN(R)COR: Horne, S.; Rodrigo, R. J. Chem. Soc., Chem. Commun. 1991, 1046-1048. Reference 7b. (f) ArN(R)SiR3: ref 7b. (g) ArN(SO2Ph)Ar′: Hellwinkel, D.; Supp, M. Chem. Ber. 1976, 109, 3749-3766. Shafer, S. J.; Closson, W. D. J. Org. Chem. 1975, 40, 889-892. (h) For an analogous migration of N-acylphenothiazines, see: Hallberg, A.; Svensson, A.; Martin, A. R. Tetrahedron Lett. 1986, 27, 1959-1962. (7) For an interesting migration in a thiophene 2-sulfonamide, see: Slocum, D. W.; Gierer, P. L. J. Org. Chem. 1973, 38, 4189-4192. (8) Detailed studies will be the subject of a full paper. See also: MacNeil, S. L. M.Sc. Thesis, University of Waterloo, 1997. (9) For reports on rearrangements of different N-groups, see refs 7d-h. 1134
entry
R
product
conditionsa
1 2 3 4 5 6 7 8 9 10 11 12 13 14
H H 3-OMe 3-OMe 4-OMe 4-OMe 3,5-OMe 3,5-OMe 3-Cl 3-Cl 4-Cl 4-Cl 2-Ph 2-Ph
8a/9a 8a/9a 8b/9b 8b/9b 8c/9c 8c/9c 8d/9d 8d/9d 8e/9e 8e/9e 8f/9f 8f/9f 8g/9g 8g/9g
A B A B A B A B A B A B A B
yield of 8, %
59 6 54 4 75 7
73 47
yield of 9, % 81 90 26b 90b 35 90 14 90 92b 94b 87 97 19 51
a Conditions: (A) 1. t-BuLi/TMEDA/-78 °C/Et O/1 h; 2. -78 °C f 2 rt. (B) 1. LDA/0 °C/THF, 2. 0 °C f rt. b Migration to the 2-position occurs. No 6-substituted product was observed.
of these favorable conditions to a series of N-carbamoyl diarylamines 7b-g, prepared in 49-94% yields by a Pdcatalyzed aryl amination protocol,12 furnished migration products 8b-g and 9b-g in good to excellent yields and regioselectivities (Table 1, entries 3, 5, 7, 9, 11, and 13). In the absence of mechanistic studies for the anionic ortho N-Fries process,11 including establishment of intramolecularity,13 a rationale for the observed regioselectivities is speculative. However, noteworthy are the following points: (a) for 7b (entry 3), regioselective migration occurs into the unsubstituted ring, which contrasts with that observed for an N,N-diisopropyl 3′-methoxybiphenyl-2 carboxamide;14 (b) for 7e (entry 9), migration takes place into the substituted (10) For C-7 DoM chemistry of N-CONEt2, 2-TMS-indole, see: Hartung, C. G.; Fecher, A.; Chapell, B.; Snieckus, V. Org. Lett. 2003, 5, 18991902. (11) For detailed optimization studies, see: Wilson, B. M.Sc. Thesis, Queen’s University, 2004. (12) See: (a) Wolfe, J. P.; Wagaw, S.; Buchwald, S. L. J. Am. Chem. Soc. 1996, 118, 7215-7216. For reviews, see: (b) Muci, A. R.; Buchwald, S. L. Top. Curr. Chem. 2002, 219, 131-209. (c) Hartwig, J. F. In Modern Arene Chemistry; Astruc, D., Ed.; Wiley-VCH: Weinheim, Germany, 2002; pp 107-168. (13) The lack of N-deprotected products and products possessing two amide substituents, one at nitrogen and one at the ortho- or ortho′-position, which would arise by an intermolecular N f C carbamoyl migration, suggests but does not prove an intramolecular mechanism for the reaction. (14) Under LDA conditions, this compound gives 1-methoxyfluoren-9one, the result of remote metalation-cyclization, see: Fu, J.-m.; Zhao, B.p.; Sharp, M. J.; Snieckus, V. J. Org. Chem. 1991, 56, 1683-1685. For an indication of the generality of this reaction, see ref 3.
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ring in agreement with the analogous in-between metalation of 3-chlorobenzamide,2a suggesting greater significance of the inductive effect of the chloro group; (c) an inductive effect of the chloro substituent may operate at longer distance, e.g., 7f (entry 11); and (d) a presumed steric effect of the phenyl group for 7g (entry 13) forces rearrangement to give mainly 8g rather than a product of remote metalation-migration into the 2-Ph substituent as may be observed in the analogous biaryl O-carbamate series.1d,15 Higher combined yields were obtained of the anthranilamides 8a-g and 9a-g compared to those observed for the anthranilates resulting from rearrangement of the corresponding N-Boc derivatives.8 This may be due to the expected greater coordination effect of carbamoyl over Boc substitutents,3 and the greater stability of 8a-g and 9a-g to nucleophilic attack of RLi reagents. Interestingly, the migration regiochemistry was found to be more predictable and thus much more synthetically useful when mediated by LDA (Table 1, entries 2, 4, 6, 8, 10, 12, and 14). Indeed, compounds 9a-g were obtained in excellent yields and regioselectivities in all but one case (entry 14). Presumably, with LDA, the thermodynamic equilibrium existing between the two anions (leading respectively to 8a-g and 9a-g) is displaced toward the formation to that which is most stable (less basic) owing to its stabilization by two substituents (PhNCONEt2 and R). As an alternative and enhanced regioselective route to the products of anionic ortho N-Fries rearrangement into the more highly substituted ring, compounds 9b,d,e (Table 1), representing 6-substituted anthranilamides of potential pharmaceutical value,16 the DoM chemistry of the readily prepared N-methyl derivative 10 was pursued (Table 2). In
1, 2, and 5) which, due to sensitivity to the alkyllithium and lithium amide conditions, could not be obtained by the Fries rearrangement (Table 1). To illustrate further potentially useful transition metal catalyzed chemistry of some products (11d-f; entries 4-6), the boropinacolate 11f, derived from the crude boronic acid by in situ treatment with pinocol (see Supporting Information), was submitted to the typical Suzuki-Miyaura cross coupling conditions and afforded compound 12 (Scheme 3), representing an interesting bi-
Scheme 3. Synthesis of Anthranilamide 12 by Suzuki-Miyaura Cross Coupling
arylamine-biaryl framework that invites further metalation chemistry. To enhance further appreciation of the N-Fries rearrangement concept, syntheses of the highly oxygenated acridone, yukodine (17), and pyranoacridone, junosidine (18) (Scheme 4), were undertaken. The route toward yukodine (17) and
Scheme 4.
Total Synthesis of Yukodine (17) and Junosidine (18)
Table 2. DoM Route to Anthranilamides 11a-f
the event, standard metalation of 10 followed by quench with an archetypical group of electrophiles furnished excellent yields of products 11a-f including those (Table 2, entries (15) For other synthetic applications, see James, C. A. Ph.D. Thesis, University of Waterloo, 1998. (16) An important example is GF120918, an acridone 1-carboxamide that has been identified as an optimized inhibitor of multidrug resistance (MDR), see: (a) Ward, K. W.; Azzarano, L. M. J. Pharmacol. Exp. Ther. 2004, 310, 703-709. (b) Hyafil F.; Vergely C.; Du Vignaud P.; GrandPerret T. Cancer Res. 1993, 53, 4595-602.
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junosidine (18),17 originally isolated from Citrus junos,18 was initiated from the N-carbamoyl diarylamine 13, readily prepared in three steps and 90% overall yield with use of key Buchwald C-N bond cross coupling technology.19 Treatment with an excess of LiTMP20 resulted in a highly regioselective (single isomer by 1H NMR) and quantitative 1135
N-Fries rearrangement to the anthranilamide 14, which, upon standard methylation, provided compound 15. Unfortunately, attempts to incorporate a second anionic step to 16 in this total synthesis with LDA, LiTMP, and alkyllithium reagents resulted only in the formation of complex mixtures of products.11,21 Hence, resorting to more classical methods, treatment of 15 with Tf2O22 smoothly gave the acridone, which upon selective deisopropylation,23 furnished, with similar efficiency, yukodine (17).24 The synthetic work was concluded by adaptation of a convenient procedure for chromene ring construction25 to afford junosidine (18) in 81% yield. The route proceeds in nine steps and 33% overall yield from commercially available 1-chloro-3,5-dimethoxybenzene and constitutes the first total synthesis of this natural product uncontaminated by its naturally occurring angular regioisomer, 5-methoxynoracronycine (19).26 In summary, we have disclosed results on a new anionic ortho N-Fries rearrangement of N-CONEt2 diarylamines to anthranylamides, 7 f 8, 9, which leads to products 8b-d,g (17) For a comprehensive review on the isolation, structural elucidation, synthesis, biochemistry, and biological activities of these and other naturally occurring acridones, see: Skaltsounis, A. L.; Mitaku, S.; Tillequin, F. In The Alkaloids; Cordell, G. A., Ed.; Academic Press: New York, 2000; Vol. 54, pp 259-377. (18) (a) Takemura, Y.; Uchida, H.; Juichi, M.; Omura, M.; Ito, C.; Nakagawa, K.; Ono, T.; Furukawa, H. Heterocycles 1992, 34, 2123-2130. (b) Juichi, M.; Inoue, M.; Sakiyama, K.; Yoneda, M.; Furukawa, H. Heterocycles 1987, 26, 2077-2079. (19) Wolfe, J. P.; Buchwald, S. L. Angew. Chem., Int. Ed. 1999, 38, 2413. (20) LiTMP was found to yield superior results to LDA for this particular transformation. See ref 12. (21) The di-OMOM ether corresponding to 15 also led to complex product mixtures. For sensitivity of MOM derivatives to strong bases, see ref 16. (22) Charette, A. B.; Chua, P. Synlett 1998, 163. (23) Sala, T.; Sargent, M. V. J. Chem. Soc., Perkin Trans. 1 1979, 25932598. (24) A sample was found to be identical with the natural product by comparison of NMR and other spectroscopic and physical data. For yukodine, see ref 19a, for junosidine, see ref 19b. (25) Chauder, B. A.; Lopes, C. C.; Lopes, R. S. C.; da Silva, A. J. M.; Snieckus, V. Synthesis 1998, 279.
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and 9a-f with good to excellent regioselectivity and in synthetically useful yields (Table 1); an alternate, highly regioselective route to 6-substituted anthranylamides, 10 f 11, has also been developed (Table 2). Furthermore, a link of the N-Fries migration to sequential DoM and SuzukiMiyaura cross coupling chemistry (11f f 12) has been established (Scheme 3) and its application to an efficient synthesis of acridone and pyranoacridone alkaloids has been demonstrated (Scheme 4). In combination with the reliable preparative route to diarylamines by Buchwald-Hartwig C-N coupling technology,27 the N f C 1,3-carbamoyl migration, particularly when linked to DoM tactics, allows regioselective construction of 6-substituted anthranilic acid derivatives which may be inaccessible by alternative methods and generally offers further enrichment of carbanionic chemistry for the regioselective elaboration of polysubstituted aromatics. Acknowledgment. NSERC Canada is acknowledged for consistent support of our synthetic programs. We thank Matthew Gray and Laura Briggs for preliminary experiments. S.M. was an NSERC Postgraduate Fellow (1994-1998), Queen’s Graduate Fellow (1998-1999), and OGS (Science & Technology) recipient (1999-2000). Supporting Information Available: Experimental procedures and full spectroscopic data for all new compounds. This material is available free of charge via the Internet at http://pubs.acs.org. OL053162E (26) Juichi, M.; Inoue, M.; Kuniko, A.; Furukawa, H. Heterocycles 1986, 24, 1595-1597. (27) Buchwald-Hartwig conditions typically afford products in higher yields, under milder conditions, than classical Ullmann conditions. For a direct comparison involving N-phenyl-4-methoxyaniline, see: Ane´mian, R.; Morel, Y.; Baldeck, P. L.; Paci, B.; Kretsch, K.; Nunzi, J.-M.; Andraud, C. J. Mater. Chem. 2003, 13, 2157-2163.
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